1. Field of the Invention PA1 2. Description of the Prior Art PA1 R.sup.4 represents an aralkyl group which may be substituted; R.sup.5 and R.sup.7 are identical or different and each represents an alkyl group; PA1 R.sup.6 represents a hydrogen atom or an alkyl group; R.sup.8 represents an alkyl group; R.sup.9 represents a hydrogen atom or an alkyl group; n and m are identical or different and each represents an integer of 0 to 6; provided that when either one of R.sup.1 and R.sup.2 is a hydrogen atom, R.sup.9 is an akyl group;
The present invention relates to a 1,4-dihydropyridine derivative, a process for the production thereof, and the pharmaceutical use thereof. More particularly, this invention relates to a novel 1,4-dihydropyridine derivative which is characterized by a strong pharmacological action such as antihypertensive action, vasodilative action, etc. and the long duration of pharmacological action, a process for the production thereof, and the pharmaceutical use thereof.
Various 1,4-dihydropyridine derivatives have hitherto been made known as compounds having such pharmacological action as antihypertensive action, vasodilative action, etc. For instance, 4-(2-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (hereinafter referred to as Nifedipine) is known to have a strong pharmacological action such as coronary vasodilative action, etc. (U.S. Pat. No. 3,644,627) and is now generally used as a remedy for angina pectoris. Though Nifedipine is a compound which has an excellent pharmacological activity, it has some demerits of being purely soluble in water, chemically very unstable, and short in durability of its pharmacological activity.
A wide variety of Nifedipine derivatives have hitherto been proposed. For example, 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester (hereinafter referred to as Felodipine) represented by the undermentioned formula is known (Japanese Patent Application Laid-Open No. 9083/'80). ##STR2## Felodipine is a 1,4-dihydropyridine derivative which has a 2,3-disubstituted phenyl group at the 4-position and has an action to selectively dilate the peripheral vascular tracts (Japanese Patent Application Laid-Open No. 9083/'80, Official Gazette p. 2, left lower section, lines 13-16). However, this compound is very purely soluble in water and its vasodilative action is not strong enough.
Another example of 1,4-dihydropyridine derivative represented by the following formula is described in Japanese Patent Application Laid-Open No. 24277/'75 ##STR3## wherein R is a hydrogen atom, or a linear or branched saturated aliphatic group; R' and R" are identical or different and each represents a hydrogen atom or an alkyl group; R.sup.2 is an aryl group (which may have 1, 2 or 3 substituents groups discretionally selected from among nitro, cyano, azido, alkyl, alkoxy, acyloxy, alkoxycarbonyl, amino, acylamino, alkylamino, dialkylamino, SOn-alkyl (wherein n=0, 1 or 2), phenyl, trifluoromethyl and halogen atoms); Q is a straight-chain, brached-chain, or cyclic saturated or unsaturated hydrocarbon chain which may discretionally contain one or two hydroxyl groups as substituents and may be interrupted discretionally by one or two oxygen atoms; R.sup.1 and R.sup.4 are identical or different and each represents a hydrogen atom or a linear or branched alkyl group; and X represents a linear or branched alkylene group.
This compound has a N,N-dialkylaminoalkoxycarbonyl group (--COO--X--NR'R") as the substituent as the 5-position. It is disclosed that this compound is capable of dilating the coronary blood vessel remarkably extending over a long period of time (Japanese Patent Application Laid-Open No. 24277/'75, Official Gazette p. 17, left lower section, lines 3-9). However, this 1,4-dihydropyridine derivative is not satisfactory enough in both antihypertensive action and duration of action, according to the study made by the inventors of the present invention.
Also, U.S. Pat. No. 3,985,758 describes, for example, 1,4-dihydropyridine derivative expressed by the following formula ##STR4## wherein R represents hydrogen or lower alkyl; R.sup.1 and R.sup.2 represent methyl respectively; R.sup.3 represents phenyl, benzyl, halobenzyl, or alkoxybenzyl; R.sup.4 represents hydrogen, methyl or ethyl; A represents lower alkylene; R.sup.5 represents methyl, or lower alkoxy, or lower alkoxy with lower alkoxy; and R.sup.6 represents nitro or trifluoromethyl.
As the most typical of such compounds, 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-.beta.-(N-benzyl-N-methylamino) ethyl hydrochloride (hereinafter referred to as Nicardipine) is especially known widely. This type of compound is structurally characterized in that it has a monosubstituted phenyl group at the 4-position and an N-alkyl-N-aralkylaminoalkoxycarbonyl group at the 5-position. U.S. Pat. No. 3,985,758 also discloses that these compounds have cerebral vascular dilator activity and high water-solubility.
However, U.S. Pat. No. 3,985,758 neither gives description as to the concrete examples of the 1,4-dihydropyridine derivative which has an N-alkyl-N-aralkylamino branched alkoxycarbonyl group at the 5-position nor makes reference to the 1,4-dihydropyridine derivative which has a disubstituted phenyl group at the 4-position. U.S. Pat. No. 3,985,758 also remains utterly silent about the duration of pharmacological actions of 1,4-dihydropyridine derivatives.
The studies made by the inventors of the present invention has revealed that the 1,4-dihydropyridine derivatives represented by Nicardipine, etc. have not strong enough pharmacological activities including an antihypertensive action, etc. and that the duration of action is not long enough either.